3D QSAR and molecular docking studies of benzimidazole derivatives as hepatitis C virus NS5B polymerase inhibitors

The urgent need for novel HCV antiviral agents has provided an impetus for understanding the structural requisites of NS5B polymerase inhibitors at the molecular level. Toward this objective, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 67 HCV NS5B polymerase inhibitors were performed using two methods. First, ligand-based 3D QSAR studies were performed based on the lowest energy conformations employing the atom fit alignment method. Second, receptor-based 3D QSAR models were derived from the predicted binding conformations obtained by docking all NS5B inhibitors at the allosteric binding site of NS5B (PDB ID: 2dxs). Results generated from the ligand-based model were found superior (r2cv values of 0.630 for CoMFA and 0.668 for CoMSIA) to those obtained by the receptor-based model (r2cv values of 0.536 and 0.561 for CoMFA and CoMSIA, respectively). The predictive ability of the models was validated using a structurally diversified test set of 22 compounds that had not been included in a preliminary training set of 45 compounds. The predictive r2 values for the ligand-based CoMFA and CoMSIA models were 0.734 and 0.800, respectively, while the corresponding predictive r2 values for the receptor-based CoMFA and CoMSIA models were 0.538 and 0.639, respectively. The greater potency of the tryptophan derivatives over that of the tyrosine derivatives was interpreted based on CoMFA steric and electrostatic contour maps. The CoMSIA results revealed that for a NS5B inhibitor to have appreciable inhibitory activity it requires hydrogen bond donor and acceptor groups at the 5-position of the indole ring and an R substituent at the chiral carbon, respectively. Interpretation of the CoMFA and CoMSIA contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. Taken together, the present 3D QSAR models were found to accurately predict the HCV NS5B polymerase inhibitory activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the benzimidazole derivatives in the data set.     

Isotopic labelling of peptides and isotope ratio analysis using LC–ICP–MS: a preliminary study

Bradykinin and substance P have been derivatised with cyclic diethylenetriaminepentaacetic anhydride (cDTPA) and subsequently labelled with natural and isotopically enriched Eu³⁺. This enabled the detection and relative quantitation of the peptides using element-selective detection by high-performance liquid chromatography inductively coupled plasma mass spectrometry (LC–ICP–MS). Relative quantitation was achieved by differentially labelling two peptide sources, after derivatisation with cDTPA, using natural and enriched ¹⁵¹Eu respectively. The ¹⁵¹Eu:¹⁵³Eu isotope ratio was measured and used to calculate the original peptide ratio. The measured ratios came within 5.2% of the known ratio. Derivatisation and chelation reactions were additionally confirmed using LC–ESI–MS.     

Partitioning Posets

Given a poset P = (X, ≺ ), a partition X ₁, ..., X _k of X is called an ordered partition of P if, whenever x ∈ X _i and y ∈ X _j with x ≺ y, then i ≤ j. In this paper, we show that for every poset P = (X, ≺ ) and every integer k ≥ 2, there exists an ordered partition of P into k parts such that the total number of comparable pairs within the parts is at most (m − 1)/k, where m ≥ 1 is the total number of edges in the comparability graph of P. We show that this bound is best possible for k = 2, but we give an improved bound, , for k ≥ 3, where c(k) is a constant depending only on k. We also show that, given a poset P = (X, ≺ ) and an integer 2 ≤ k ≤ |X|, we can find an ordered partition of P into k parts that minimises the total number of comparable pairs within parts in time polynomial in the size of P. We prove more general, weighted versions of these results. Supported by an EPSRC doctoral training grant.     

Cutting two graphs simultaneously

Consider two graphs, and , on the same vertex set V, with and having edges for . We give a simple algorithm that partitions V into sets A and B such that and . We also show, using a probabilistic method, that if and belong to certain classes of graphs, (for instance, if and both have a density of at least 2/, or if and are both regular of degree at most with n sufficiently large) then we can find a partition of V into sets A and B such that for . © 2007 Wiley Periodicals, Inc. J Graph Theory 57: 19–32, 2008     

Detection of methyl salicylate using polymer-filled chemicapacitors

Methyl salicylate (MeS) is used as a chemical warfare agent simulant to test chemical protective garments and other individual personal protective gear. The accurate and real-time detection of this analyte is advantageous for various testing regimes. This paper reports the results of MeS vapor exposures on polymer-filled capacitance-based sensors at temperatures ranging from 15 °C to 50 °C under dry and humid conditions. Multiple capacitors were arranged in an array on a silicon chip each having a different sorptive polymer. The sensors used parallel-plate electrode geometry to measure the dielectric permittivity changes of each polymer when exposed to water and MeS vapor. Of the four polymers tested against MeS, the optimal polymer displayed near or sub-parts-per-million detection limits at 35 °C (0–80%RH).     

Synthesis of biphenyl anilines using iodo phenylformamides via a one-pot Suzuki coupling reaction

We have developed a novel and economical synthesis of biphenyl anilines via a one-pot Suzuki coupling reaction with iodo phenylformamides. This literature is an unprecedented approach to biphenyl anilines replacing costly aminophenylboronic acids with economical iodo anilines for the preparation of biphenyl anilines. It also provides a viable synthesis toward substituted biphenyl anilines where the required aminophenylboronic acids are not readily available.     

Complexities associated with moisture in foamed polysiloxane composites

An understanding of mechanisms of moisture outgassing from silicones and the impact on material mechanical properties is important for compatibility and life prediction in sealed systems containing these materials. A series of thermomechanical (TMA) stress relaxation experiments have been performed to provide information on the important load bearing properties of these materials as a function of time and temperature. Two different silica reinforced foamed polysiloxane materials were tested, a peroxide cured rubber (M97) and a condensation-cured elastomer (S5370). The M97 foam showed unexpectedly complex stress relaxation profiles at temperatures around 100 °C, whereas the S5370 samples showed the expected smooth stress decay behaviour. Dried M97 foam samples show different stress relaxation behaviour to the non-dried materials. Furthermore, stress relaxation studies performed in controlled humidity environments showed that moisture has a significant accelerating influence on the underlying relaxation process. In dry regimes, a reduced stress relaxation rate was observed, with an increase in the force required to maintain a given amount of compression on the sample. To further develop our understanding of the effects of moisture, we have exposed samples to water enriched to 40% in ¹⁷O and used ¹⁷O nuclear magnetic resonance (NMR) spectroscopy to assess labelled hydrolysis reaction products. Our studies show that Si-¹⁷O-Si hydrolysis products are readily incorporated in the polymer and the degradation is enhanced by the influence of gamma radiation and/or heat. In addition, the polysiloxane foams showed different age related trends in sealed (where moisture is retained) and ventilated (open-to-air) regimes. Our observations have been explained by moisture influencing both physical and chemical degradation processes. Our findings on moisture induced changes in silicone stress relaxation rates are novel and demonstrate the importance of controlling humidity in service applications involving these materials.     

The effect of sequence on the conformational stability of a model heteropolymer in explicit water

We investigate the properties of a two-dimensional lattice heteropolymer model for a protein in which water is explicitly represented. The model protein distinguishes between hydrophobic and polar monomers through the effect of the hydrophobic monomers on the entropy and enthalpy of the hydrogen bonding of solvation shell water molecules. As experimentally observed, model heteropolymer sequences fold into stable native states characterized by a hydrophobic core to avoid unfavorable interactions with the solvent. These native states undergo cold, pressure, and thermal denaturation into distinct configurations for each type of unfolding transition. However, the heteropolymer sequence is an important element, since not all sequences will fold into stable native states at positive pressures. Simulation of a large collection of sequences indicates that these fall into two general groups, those exhibiting highly stable native structures and those that do not. Statistical analysis of important patterns in sequences shows a strong tendency for observing long blocks of hydrophobic or polar monomers in the most stable sequences. Statistical analysis also shows that alternation of hydrophobic and polar monomers appears infrequently among the most stable sequences. These observations are not absolute design rules and, in practice, these are not sufficient to rationally design very stable heteropolymers. We also study the effect of mutations on improving the stability of the model proteins, and demonstrate that it is possible to obtain a very stable heteropolymer from directed evolution of an initially unstable heteropolymer.     

HPTLC determination of rabeprazole and domperidone in capsules and its validation

This paper describes a validated high-performance thin-layer chromatography (HPTLC) method for simultaneous estimation of rabeprazole (RA) and domperidone (DO) in pure powder and in capsule formulations. An HPTLC method separation is achieved on an aluminum sheet of silica gel 60F(254) using ethyl acetate-methanol-benzene-acetonitrile (30:20:30:20 v/v) as mobile phase. Quantitation is achieved with UV detection at 287 nm over a concentration range of 400-1200 ng/spot and 600-1800 ng/spot with mean recovery of 99.82 +/- 0.74 and 99.43 +/- 0.68 for RA and DO, respectively, in the HPTLC method. This method is simple, precise, and sensitive, and it is applicable for the simultaneous determination of RA and DO in pure powder and in capsule formulation.     

Studies in synthesis of furoflavones possessing anti‐cancer activity

Several new furoflavanones (3a‐3I) have been synthesized from the in‐situ generated chalcones by the reaction of ortho‐hydroxy acetyl benzofuran and aryl aldehyde in presence of piperidine. Ethanolic sodium hydroxide (1%) gave chalcones (2a‐2I) as the exclusive product. Flavindogenides (3‐arylidene flavanones) (5a‐5d) have been isolated as the co‐product along with chalcones and flavanones in cases where excess of aryl aldehyde was used. The stereochemistry of 3‐arylidene flavanones has been established by the preparation of both Z (6) and E (5a‐5d) diastereomers. Single crystal X‐ray diffraction data shows the flavanone ring to exist in quasi chair conformation with phenyl ring equatorial. Furoflavanones were finally dehydrogenated to furoflavones (4a‐4I) using DDQ (2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone). The compounds have been screened for in‐vitro cytotoxicity against human cancer cell lines.